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Postnatal growth of the ventral prostate in Wistar ratsA stereological and morphometrical study.

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Postnatal Growth of the Ventral
Prostate in Wistar Rats: A Stereological
and Morphometrical Study
Department of Cell Biology, Institute of Biology, State University of Campinas,
Campinas, São Paulo, Brazil 2Department of Biology, IBILCE/UNESP,
São José do Rio Preto, São Paulo, Brazil
Morphological and stereological analyses were used to characterize the
growth kinetics of the Wistar rat ventral prostate (VP). Volume density and
absolute volume of the epithelium, lumen, smooth muscle cells (SMCs), and
nonmuscular stroma were determined by stereology and paired with
plasma testosterone levels and different morphometric measurements. The
VP shows an initial growth within the first 3 weeks, a resting phase, and the
puberal growth. The puberal growth was coincident with the raise in
plasma testosterone. Lumen formation occurred within the 3 postnatal
weeks. After an expected increase during puberty, the lumen showed a
further increase at the 12th week. The volume density of the nonmuscular
stroma and of the SMCs decreased slowly postnatally. Absolute volume of
the luminal compartment showed three phases of growth (weeks 1–3, 6 –9,
and 11–12). On the other hand, the increase in the absolute volume of the
epithelium was steady up to the 8th week and then showed a marked
increase up the 10th week. The increase in epithelial volume was characterized morphologically by the presence of epithelial infoldings and sprouts.
The growth of the epithelium showed a 2-week delay as compared to the
lumen and occurred only until the 10th week. The epithelial height was
variable but could be related to the synthetic activity of the epithelium. In
conclusion, the postnatal growth of the VP results from a combination of
epithelial proliferation/differentiation and synthesis/accumulation of the
secretory products in the lumen. Anat Rec Part A, 288A:885– 892, 2006.
2006 Wiley-Liss, Inc.
Key words: epithelial growth; prostate development; prostate
secretory activity; rat ventral prostate; stereology
Prostatic morphogenesis is not determined by the genetic sex, but by exposure to androgens. It is dependent on
the androgen production by the testis in the fetus (Pointis
et al., 1980; Cunha et al., 1987) and androgen insensitivity
hinders prostatic development. It has also been demonstrated that the urogenital sinus of female and male may
form functional prostatic tissue if it is properly stimulated
by androgen at the correct embryonic stage (Takeda et al.,
Epithelial budding of the rodent prostate is initiated at
about the 17.5 day postcoitum (Timms et al., 1994). Even
though testosterone is the androgen produced by the fetal
testis, dihydrotestosterone (DHT) is responsible for the
prostatic morphogenesis (Taplin and Ho, 2001). DHT is
produced by the urogenital sinus by the enzyme 5-␣ reductase. This enzyme has been detected in the urogenital
Grant sponsor: Fundação de Amparo à Pesquisa do Estado de
São Paulo; Grant number: 04/05498-8
*Correspondence to: Hernandes F. Carvalho, Department of
Cell Biology, Institute of Biology, State University of Campinas
(UNICAMP), CP6109, 13083-863 Campinas, SP, Brazil. Fax: 5519-3788-6111. E-mail:
Received 11 May 2006; Accepted 22 May 2006
DOI 10.1002/ar.a.20363
Published online 11 July 2006 in Wiley InterScience
sinus and external genitalia of rats, rabbits, and humans
(Wilson et al., 1983) and its deficiency results in the anomalous growth of the external genitalia and complete absence of the prostate.
The epithelial differentiation in the prostate takes place
in parallel to the development of the stroma. Androgens
act on androgen receptors in the urogenital mesenchyme
to induce epithelial proliferation, ductal branching, and
differentiation of the epithelial cells (Cunha et al., 1987,
1992; Marker et al., 2003). In turn, the developing epithelium directs the differentiation of the smooth muscle
(Hayward et al., 1998). Neither epithelium nor smooth
muscle is capable to develop in the absence of each other
(Hayward and Cunha, 2000). During organogenesis, one of
the functions of the androgens is to maintain the smooth
muscle that surrounds the urethra as a thin layer (Thomson et al., 2002). If the smooth muscle layer is thick, as it
occurs in the female, the initial budding from the urethra
cannot reach the urogenital sinus mesenchyme and there
is no development of the prostate gland (Thomson et al.,
The subsequent ductal morphogenesis, canalization,
and epithelial differentiation also depend on androgens
and take place in association with a transient perinatal
increase in the serum testosterone concentration (Donjacour and Cunha, 1988).
The neonatal prostate is sensible to androgens. Testosterone administration accelerates prostatic growth, and
adult size may be reached much earlier (Berry and Issacs,
1984). On the other hand, neonatal castration inhibits
pubertal prostatic growth and development, and this effect may be reversed by testosterone (Cunha et al., 1987;
Corbier et al., 1995). During puberty, there is an additional increment of the prostatic weight and a slight increase in the number of ductal branches (Sugimura et al.,
1986). This suggests that the prostate is sensitive to the
low levels of androgens for the ductal branching and that
the response to the increasing levels of testosterone during puberty is different from the initial response (Hayward and Cunha, 2000).
A detailed study of the postnatal growth considering the
different tissue compartments is still lacking for the rat
ventral prostate, while it has been extensively studied in
the mouse (Singh et al., 1999). Furthermore, the rat ventral prostate has also been demonstrated to be adequate
for the testing of endocrine disruptors, given its extreme
dependency on androgen stimulation and high susceptibility to estrogenic stimulation (Prins et al., 2001; Putz et
al., 2001a, 2001b).
Given the usefulness of rat ventral prostate in environmental risk assessment, the demonstration of strain-specific variations, the sensibility of prostatic development
and function to androgen stimulation, and disturbance by
steroid compounds, we have found it reasonable to undertake a detailed analysis of the prostatic development in
Wistar rats, trying to define morphological and stereological parameters for the main tissue compartments from the
first postnatal week to adulthood.
Pursuing this task, we have employed a series of analyses, which demonstrated the differential kinetics of the
prostatic compartments in postnatal life and an alternation between proliferative and secretory states of the epithelium that culminates in prostatic growth.
Animal Protocol
Sixty male Wistar rats were obtained from Centro Multidisciplinar para Investigação Biológica (CEMIB)/State
University of Campinas. Groups of five animals were used
for each time point and for the different analyses. They
were maintained in a controlled environment with free
access to food and water. Experiments were performed
according to the Guide for Care and Use of Laboratory
Animals. Rats were weighed and sacrificed by cervical
dislocation. The ventral prostate was carefully dissected
out, weighed, and fixed.
Serum Testosterone Quantification
Blood samples were collected either after decapitation
or cardiac punction. Serum testosterone was quantified
using a modular chemiluminescence immunoassay analyzer ECi (Johnson and Johnson) according to Weeks and
Woodhead (1984). Triplicate measurements were performed for each sample and serum samples from three
animals were used for each time point and serum samples
were assayed in duplicate. The sensitivity of the test was
0.94 ng/dL. The intra-assay and interassay variations
were 5.36% and 5.10%, respectively.
The ventral prostate was immediately fixed by immersion in 4% formaldehyde in phosphate-buffered saline
(PBS) for 24 hr. Samples were then washed, partially
dehydrated, and embedded in Leica historesin. Two micrometer sections were obtained and stained with hematoxylin and eosin (Behmer et al., 1976).
Stereological Analyses and Morphometry
Six microscopical fields from the hematoxylin and eosinstained sections from three animals for each group were
photographed and subjected to stereology using Weibel’s
system and a 168-point grid as applied to the ventral
prostate by Huttunen et al. (1981) and employed previously (Garcia-Florez et al., 2005). The volume density (Vv)
of the epithelium, lumen, smooth muscle, and nonmuscular stroma was determined. The nonmuscular stroma corresponded to everything besides the epithelial structures
but the smooth muscle cells (Garcia-Florez et al., 2005).
The total stroma was the sum of the smooth muscle and
nonmuscular stroma. The volume (or absolute volume) of
each of these compartments was determined by multiplying the volume density by the mean prostatic weight
based on the determination that 1 mg of fresh rat ventral
tissue had a volume of approximately 1 mm3 (DeKlerk and
Coffey, 1978).
The epithelial cell height was measured on hematoxylin
and eosin-stained sections using the Image Pro Plus software (Media Cybernetics, Silver Springs, MD) after digitalization of the microscopical images. Calibration was
done using an Olympus graded microscopical slide. Seventy-five measurements were done for each experimental
Mitotic Cell Frequency
Historesin sections were subjected to the Feulgen’s reaction. They were hydrolyzed with 4 N HCl for 1 hr 15 min
and then reacted with Schiff’s reagent for 40 min, followed
Fig. 2. Plasma testosterone concentration (ng/mL) along the 12
postnatal weeks (mean ⫾ SEM; n ⫽ 5).
Fig. 1. Body weight of normal rats during the first 12 postnatal
weeks. Values are in grams (mean ⫾ SEM; n ⫽ 5).
by extensive washing, dehydration in ethanol, and mounting in Canada’s balsam (Márquez et al., 2001). Forty fields
were taken at random and the mitotic figures were
counted (15 fields per animal; three animals).
Body Weight and Testosterone Levels
There was a continuous increment of body weight in the
rats employed in this work (Fig. 1). This growth continued
from the first to the ninth week and plateaued at about
250 g. The serum testosterone concentration was low (⬃
0.75 ng/mL) until the fifth week, raised to 1.5–2.0 ng/mL
from the sixth to the eighth week, then leveled at ⬃ 3.5
ng/mL by the ninth week (Fig. 2). A greater variation in
the serum testosterone level was observed in the early
adult life, as demonstrated by oscillation of the mean
concentration, as well as by the larger SEM.
Ventral Prostate Growth and Histological
Fig. 3. Weekly variation in absolute and relative weight of rat ventral
prostate from the 1st to the 12th week of postnatal development. Organ
absolute weights are represented as grams (inset) and relative weights
are represented as the ratio of prostatic to total body weight (mean ⫾
SEM; n ⫽ 5).
The ventral prostate showed an initial postnatal
growth, a resting period from the fourth to the sixth week,
and a pubertal growth up to the adult size (Fig. 3). The
resting period observed in the relative weight was not so
evident when the absolute weight of the gland was taken
into account (Fig. 3, inset), indicating the presence of a
somatotrophic growth before puberty.
From the first to the third week, there was a definition
of the lumen (Fig. 4a– c), which was filled with secretory
material. The formation of the lumen was coincident with
the differentiation of the epithelial cells, which formed
mostly solid cords by the first week (Figs. 4a and 5a) and
became progressively polarized and organized in a single
layer (Figs. 4b and c and 5b). The stroma was reduced and
exhibited decreased cell density. From the 3rd to the 6th
weeks, no change in histological organization was evidenced (Fig. 4d–f). However, by the sixth week, we observed the presence of some images of epithelial infoldings
and sprouts. These latter became more evident later on
(Figs. 4f–i and 5c and d) and consisted of projections of
groups of epithelial cells toward the stroma. Smooth muscle cells (SMCs) were excluded from their surface but
fibroblasts were commonly observed. From the 10th to the
12th weeks, there was an engorgement of the lumen, with
corresponding distension of the epithelium, i.e., disappearance of foldings and sprouts (Figs. 4j–l and 5e and f).
Variations of the epithelial height were noticed and
quantified. The measurements of epithelial height are
shown in Figure 8. After a progressive increase up to the
sixth week, there was a marked drop in the mean epithelial height, followed by another increase to the maximum
epithelial height. The polarized cell with a large, faintly
stained supranuclear area (corresponding to the Golgi
complex) was observed throughout (Fig. 5b, e, and f).
The volume densities of the different prostatic compartments (Fig. 6) confirmed some of the histological observa-
Fig. 4. Histological organization of rat ventral prostate from the 1st to the 12th week of postnatal
development (a–l, respectively). The arrows indicate small alveoli or sites of epithelial sprouting. The
arrowheads point to regions of epithelial infolding. Scale bars ⫽ 100 ␮m.
tions. The formation of the lumen took place within the
first 3 weeks. The lumen then became the predominant
compartment in the prostate. The proportion between the
volume of the lumen to that of other compartments was
maintained up to the eighth week, when it showed a
further increase, reaching as much as 70% of the prostatic
volume density. The volume density of the stroma decreased from the first to the second week, remained constant up to the eighth week, then decreased again from
the eighth to the ninth week. The volume density of the
smooth muscle cells showed a similar behavior. The sec-
ond drop in the volume density of the stroma, which took
place after the eighth week, counterbalanced with an increase in the volume density of the epithelium.
The estimation of the absolute volume for the different
compartments clearly showed the contribution of both epithelium and lumen to the growth of the prostatic gland
(Fig. 7). After the formation of the lumen within the first
3 weeks, there was a prominent growth of this compartment after the sixth week. This was then followed by an
increase in the epithelial compartment, which was observed after the eighth week. The absolute volume of both
Fig. 5. Details of the prostatic epithelium during the postnatal development. a: The epithelium in the 1-week-old rat is composed mainly of
solid cord. The arrows point to mitotic cells in the epithelium and stroma.
b: By the second week, the proximal areas of the epithelium present
differentiated cells and a completely formed lumen. The arrow points to
a mitotic epithelial cell. c and d are aspects of epithelial sprouting
observed at the sixth and seventh weeks, respectively. The arrowheads
delineated the sproutings, which are characterized by epithelial projections toward the stroma. The SMCs are excluded from the sprouting
area, while fibroblasts (F) were commonly seen in this region. e: The
epithelial cells in the prostate of a 10-week-old rat are tall and organized
in a single layer. They present a prominent supranuclear chromophobic
area (arrow). f: The epithelial cells in the prostate of a 12-week-old rat
preserve the well-developed supranuclear chromophobic area (arrow).
Ep, epithelium. Scale bars ⫽ 10 ␮m (a, b, e, and f); 25 ␮m (c and d).
Fig. 6. Volume density variation for the different prostatic compartments (epithelium, lumen, stroma, and smooth muscle cells) along the
postnatal development as determined by stereology (mean ⫾ SEM; the
number of animals employed was three).
Fig. 7. Absolute volume variation analysis for the different prostatic
compartments (epithelium, lumen, stroma, and smooth muscle cells)
along the postnatal development as determined by stereology (a). b and
c show expended views of the graph sections with data obtained for
epithelium and smooth muscle cells (mean ⫾ SEM; the number of
animals employed was 3).
Fig. 9. Frequency of mitotic figures in rat ventral prostate sections
along the postnatal development. Values correspond to the number of
mitotic figures per microscopic field. (mean ⫾ SEM) counted on 45 fields
taken from three animals.
Fig. 8. Weekly variation in epithelial cell height (mean ⫾ SEM values)
of rat ventral prostate from 1st to 12th week of postnatal development.
Values are in micrometers.
compartments plateaued at the 9th and 10th weeks, respectively, but the lumen showed a further increase at the
12th week. The smooth muscle cells also showed a contribution to the overall increase in prostatic volume, with a
pattern very similar to the epithelium, but anticipating it,
with the pubertal growth beginning at the sixth week.
Figure 8 shows the variation in epithelial cell height
along the 12 postnatal weeks. Increases in epithelial
heights started at the fourth postnatal week, preceding
the increase in testosterone concentration in the plasma.
Cell Proliferation
The frequency of mitotic cells was also evaluated. The
number of mitotic cells per microscopical field showed an
initial peak at the second postnatal week and a second one
at the sixth week. This second peak showed a slow decline
up to the 10th week. Mitotic cells were rare at the 5th,
11th, and 12th weeks (Fig. 9).
This article presents a detailed analysis of the postnatal
growth of the rat ventral prostate. It was demonstrated
that the ventral prostate (VP) grows progressively after
birth. Since most of the prostatic growth in rodents occurs
after birth, the prostate is adequate for studies of occupational exposition to a series of steroidal compounds. In this
sense, the adequate characterization of prostatic development seems necessary, specially to avoid strain-specific
variations (Putz et al., 2001a). Furthermore, the postnatal
growth is complex, and we thought that the characterization of growth kinetics of the different tissue compartments could contribute to the knowledge of prostatic physiology.
After the early postnatal increase in prostatic weight, a
resting period was observed between the fourth and sixth
week, in which the growth follows the general body growth
and precedes the pubertal growth initiated at the seventh
week. As expected (Banerjee et al., 1994), testosterone
sets the growth response of the organ. In addition, it was
observed that prostatic size increases in parallel to the
overall body weight, indicating a somatotrophic regulation.
A remarkable phenomenon taking place within the first
3 weeks is the formation of the lumen, which then becomes
the predominant tissue compartment of the organ. This
aspect, as well as the proliferative response and branching
of the epithelium, results from testosterone surge, taking
place immediately after birth (Corbier et al., 1995). It is
interesting to note that the peak of prostate growth at the
third week occurs 1 week after the observed peak of cell
proliferation, demonstrating that cell growth and the accumulation of secretory material in the lumen contribute
to the observed increase in weight. The epithelial proliferation observed within the first 3 postnatal weeks reproduced a similar event reported before for the mouse
(Weihua et al., 2002).
The volume density of the epithelium was kept approximately the same until the eighth week. Thereafter, there
was an increase in the epithelium, which is compensated
by an equivalent reduction in the volume density of the
stroma. These two events revealed a progressive involvement of the gland with secretory activity. They also illustrates that the VP shows a two-phase response to the
increasingly testosterone levels during puberty. First,
there is a clear activation of the secretory activity, manifested by the increase in the absolute volume of the lumen,
then a delayed increase in the volume of the epithelium,
which takes place 2 weeks later. The variation in the
absolute volume confirmed these observations.
To our understanding, this growth pattern is due to two
rather distinct responses. The raising testosterone levels
stimulate the secretory activity of the existing epithelial
cells. The growth of the lumen is immediate, given the
accumulation of secretory material produced by the epithelium. Then, the same rise in plasma testosterone stim-
Fig. 10. Schematic diagram of the selected events detected during the 12 weeks of rat ventral prostate
ulates a second set of (basal?) epithelial cells to proliferate
and then to differentiate. Proliferation and differentiation
of the epithelium occurs within the 2-week period between
the increase in the lumen and the manifested increase in
epithelial volume.
It may also be considered that the increase in epithelial
volume is initiated at the sixth week by the proliferative
response of the epithelial cells and only observed 2 weeks
later, after their growth and differentiation. This is suggested by the peak of mitotic activity in the epithelium at
the sixth week, coincident with the rise in testosterone
This pubertal peak of cell proliferation is secondary to a
higher peak observed at the second week. The pattern of
mitotic activity demonstrates that the two main phases of
prostatic growth results at least in part from epithelial
cell proliferation. The occurrence of mitotic cells correlates
well with previous findings on the distribution of 3Hthymidine incorporation in the ventral prostate of
Sprague-Dawley rats (Banerjee et al., 1991), which
showed an increase in proliferating cells at about the sixth
week (45 days) in the intermediate region, but not in the
distal region. Even though we have not distinguished be-
tween the ductal regions, these findings allow the conclusion that the two main phases of prostatic growth results
at least in part from epithelial cell proliferation.
Another important observation of this work was the
remodeling of the epithelium in response to the increased
cell number. It seems that the new cells are organized as
both epithelial infoldings and sprouts. Both structures
appear as intermediated states of epithelial organization,
since they virtually disappeared by the eighth week. We
suggest that these structures are resolved by distension of
the epithelial acini, likely in response to the accumulation
of secretory material in the lumen. However, sprouts seem
to require localized stromal reorganization, as they project
toward the stroma. The exclusion of SMCs from the sprout
region seems to correlate with this stromal remodeling.
Further studies are necessary to evaluate these changes
and to determined their similarity to the budding taking
place much earlier.
It seems that the accumulation of secretion in the lumen
results in a marked predominance of this compartment at
the 12th week. This in turn results in a decrease of the
epithelial compartment, perhaps by a negative effect of
the accumulated secretion on the synthetic activity. How-
ever, there was not any variation in the epithelial height
from the 9th to the 12th week. As mentioned above, this
increase in the lumenal volume is associated with the
disappearance of the epithelial infoldings and sprouts observed at the seventh week.
The present results then suggest that prostatic growth
is characterized by a two-phase phenomenon. First, there
is a proliferative response with the formation of epithelial
infolding and/or sprouting. Second, there is a marked increase in the accumulation of secretion in the lumen due
to the stimulation of the synthetic activity. This biphasic
growth pattern was also observed for the female Mongolian gerbil prostate after experimental testosterone administration (Santos et al., 2006).
However, the present results suggest that the pubertal
growth of the ventral prostate of male rats is characterized by a secretory-proliferative-secretory response of the
epithelium to the rising serum testosterone concentration.
It is worth mentioning that the absolute volume of the
smooth muscle cells also increases during puberty and
decreases again after the eighth week. We cannot ascertain at the moment whether this variation reflects a variation in the number of the smooth muscle cells, the hyperthrophy of preexisting cell, or a combination of both.
The definition of the factors involved in this increase in
the smooth muscle cell absolute volume is certainly important for the characterization of the VP physiology and
will require further examination. Figure 10 summarizes
the main events of the postnatal development of the rat
ventral prostate.
Finally, this work will certainly be useful for the investigation of factors affecting prostatic growth as they define
morphological and stereological parameters that might be
considered for future studies at the cellular and molecular
levels, as well as during testing of endocrine disruptors.
The authors thank Luiz Roberto Falleiros Junior (Microscopy Center, IBILCE) and Rosana Silistino de Souza
(Morphology Laboratory, IBILCE) for technical assistance
and Manuel Garcia Florez for helpful comments and discussions. This study is part of P.S.L.V.’s PhD thesis.
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